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The molecular basis for the prothrombotic state in sickle cell disease.

ABSTRACT: The genetic and molecular basis of sickle cell disease (SCD) has long since been characterized but the pathophysiological basis is not entirely defined. How a red cell hemolytic disorder initiates inflammation, endothelial dysfunction, coagulation activation and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a history of VTE. Here, we thoroughly review the molecular basis for the prothrombotic state in SCD, specifically highlighting emerging evidence for activation of overlapping inflammation and coagulation pathways, that predispose to venous thromboembolism. We share perspectives in managing venous thrombosis in SCD, highlighting innovative therapies with the potential to influence the clinical course of disease and reduce thrombotic risk, while maintaining an acceptable safety profile.

SUBMITTER: Shet AS

PROVIDER: S-EPMC7556662 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The molecular basis for the prothrombotic state in sickle cell disease.

Shet Arun S AS Lizarralde-Iragorri Maria A MA Naik Rakhi P RP

Haematologica 20201001 10

The genetic and molecular basis of sickle cell disease (SCD) has long since been characterized but the pathophysiological basis is not entirely defined. How a red cell hemolytic disorder initiates inflammation, endothelial dysfunction, coagulation activation and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a hi ...[more]

PMID: 33054077

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Project description:The novel severe acute respiratory syndrome viral disease outbreak due to SARS-CoV-2 is a rapidly evolving disease and represents one of the greatest medical challenges in recent times. It is believed that SARS-CoV-2 has migrated from bats to an intermediate host and then to humans. This article aims at the mechanism and management of prothrombotic state in COVID-19 positive patients. We tried to present how the SARS-CoV-2 virus can induce thromboembolic events and the incidence of these thromboembolic events. We also tried to depict anticoagulation management in these patients as well as postdischarge plan and follow-up. Invasion of type 2 pneumocytes by the SARS-CoV-2 virus is critical in the course of illness because it results in activation of immune cells leading to elevation of cytokines. The subsequent activation of T cells and macrophages infiltrates the infected myocardial cells causing direct myocardiocyte toxicity and development of arrhythmia. Hypoxia or hypotension during the clinical course causes a mismatch between myocyte oxygen supply and workload demand resulting in cardiac distress. SARS-CoV-2 affects endothelial cells and pericytes that lead to severe micro and macrovascular dysfunction, and together with oxygen supply-demand mismatch, immune hyperresponsivity can potentially cause destabilization and plaque rupture causing acute coronary syndromes. Other mechanisms of injury include myocarditis, pericarditis, stress cardiomyopathy, vasculitis, and DIC (Disseminated intravascular coagulation)/microthrombi. SARS-CoV-2 enters the cells by the Spike protein S whose surface unit, S1, binds to the ACE2 receptor on the host cell. The type II transmembrane serine proteases TMPRSS2 and histone acetyltransferases (HAT) are host cell proteases that are recruited by the virus to cleave ACE2 surface protein S which facilitates the viral entry. Therefore, TMPRSS2 and HAT could be targeted for potential drugs against SARS-CoV-2. SARS-CoV-2 uses an RNA-dependent RNA polymerase for proliferation, which is targeted by remdesivir that is currently approved for emergency use by Food and Drug Administration (FDA). We need to adopt a multifaceted approach when combating SARS-CoV-2 because it presents several challenges including medical, psychological, socioeconomic, and ethical. COVID-19 is the biggest calamity during the 21st century, we need to have a keen understanding of its pathophysiology and clinical implications for the development of preventive measures and therapeutic modalities.

Project description:Background and aimsChildren with sickle cell disease (SCD) have an increased risk of multiple hemotransfusions and this can predispose them to elevated iron stores. The objectives of the study were to determine the extent of elevated iron stores and the associated risk factors in a population of steady-state SCD children in Ghana.MethodsThis cross-sectional study was conducted at the pediatric sickle cell clinic at the Komfo Anokye Teaching Hospital. Complete blood count and serum ferritin assay were performed for (n = 178) steady-state SCD children. Descriptive and multivariate logistic regression analysis were performed. Elevated iron stores were defined as serum ferritin levels >300 ng/ml. Statistical significance was considered at p < 0.05.ResultsThe mean (standard deviation) age of the participants was 9.61 (±4.34) years, and 51% of them were males. About 17% of SCD children had elevated iron stores and receiving at least three hemotransfusions during the last 12 months was strongly associated with elevated iron stores (p < 0.001). History of chronic hemotransfusion increased the odds of having elevated iron store (adjusted odds ratio [aOR] = 11.41; 95% confidence interval [CI] = 3.11-30.85; p < 0.001) but SCD patients on hydroxyurea treatment had reduced-odds of having elevated iron stores (aOR = 0.18; 95% CI = 0.06-0.602; p = 0.006). Moreover, red blood cell (Coef. = -0.84; 95% CI = -0.37, -1.32; p = 0.001), hemoglobin (Coef. = -0.83; 95% CI = -0.05, -1.61; p = 0.04), hematocrit (Coef. = -0.85; 95% CI = -0.08, -1.63; p = 0.03), mean cell volume (Coef. = 0.02; 95% CI = 0.01, 0.03; p = 0.001) and mean cell hemoglobin (Coef. = 0.04; 95% CI = 0.01, 0.07; p = 0.002) could significantly predict serum ferritin levels.ConclusionThe magnitude of elevated iron stores was high among children with SCD in steady-state. Red cell indices could provide invaluable information regarding the risk of elevated iron stores. SCD children who have a history of chronic hemotransfusion or had received at least three hemotransfusions in a year should be monitored for elevated iron stores.

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The molecular basis for the prothrombotic state in sickle cell disease.

Publications

The molecular basis for the prothrombotic state in sickle cell disease.

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